The long-term objective of this broad-based, multidisciplinary research program in diabetes is to understand the mechanism of noninsulin-dependent diabetes mellitus (NIDDM). This major new effort of East Carolina University is possible because of the availability of: 1) methods for detailed in vitro studies of insulin action and metabolism in human liver, muscle, and adipose tissue; and 2) methods to isolate lipoprotein subfractions and to examine their interactions with macrophages and skin fibroblasts. These technical advances are of maximal value only if they can be applied to a well defined population of patients with and without NIDDM. In the last three years, the Department of Surgery has performed the same gastric bypass procedure in over 300 morbidly obese patients, from whom intraoperative tissue biopsies can be obtained. These patients comprise an interesting population of whom 27% have NIDDM, 20% have impaired glucose tolerance, and the remainder have normal glucose tolerance. Furthermore, over 75% of NIDDM patients are able to maintain euglycemia, following gastric bypass, without drug therapy. Thus, the following objectives can be pursued in this program: 1) To study the mechanism(s) of insulin action at the cellular level in the liver, muscle, and adipose tissue in NIDDM, obese, and nonobese subjects, and to correlate these in vitro data with in vivo assessment of insulin sensitivity; 2) To determine in obese patients the relative distribution of plasma lipoprotein subpopulation and their interaction with macrophages and skin fibroblasts, and correlate these findings with insulin sensitivity as assessed by in vitro and in vivo experimental approaches; 3) To determine the effects of gastric bypass and subsequent predictable weight loss in morbidly obese subjects with and without NIDDM on in vivo and in vitro insulin sensitivity, and determine the effects of glycemic control on lipoprotein metabolism. It is hoped that this work will establish the cellular basis of the pathogenesis of NIDDM and help to develop a more rational therapeutic approach to this major health problem.